In this review we analyze the multi-faceted role that B cells play in the pathogenesis of rheumatoid arthritis and discuss how this information can be used to guide more specific targeti
Trang 1There is significant evidence arising from experimental models that
autoantibodies play a key role in the pathogenesis of inflammatory
arthritis In addition to autoantibody production, B cells efficiently
present antigen to T cells, produce soluble factors, including
cyto-kines and chemocyto-kines, and form B cell aggregates in the target
organ of rheumatoid arthritis In this review we analyze the
multi-faceted role that B cells play in the pathogenesis of rheumatoid
arthritis and discuss how this information can be used to guide
more specific targeting of B cells for the therapy of this disease
Introduction
The advent of biological therapy has provided a powerful tool
to improve our understanding of the pathogenesis of disease
As well as benefiting patients, the success of targeted
biological therapies demonstrates the importance of particular
molecules or cells in disease pathogenesis The potent
efficacy of rituximab, a B-cell depleting agent, in the treatment
of patients with rheumatoid arthritis (RA) has revitalized
interest in the central role played by B cells in disease
pathogenesis [1] (Fig 1)
Accumulation of B cells in the synovium is
driven by a variety of signals
RA is one of only a few diseases in which ectopic germinal
centre-like structures can be observed at the site of
inflammation [2] These structures, which range from loose
aggregates of T and B cells to distinct follicle-like structures,
are often observed in close contact with the inflamed synovial
membrane of RA patients A variety of cells, including
fibro-blast-like synoviocytes and dendritic cells, that are present in
the synovium of patients with RA produce factors that affect
B-cell survival, organization and trafficking, such as B
cell-activating factor of the TNF family (BAFF), CXC chemokine
ligand (CXCL)13, CXCL12 and lymphotoxin beta (Table 1)
[2-4] Based on their immunological function and location, each of these factors could contribute to the recruitment and maintenance of B cells in arthritic joints, thus representing potential therapeutic targets For example, blockade of surface lymphotoxin using a decoy lymphotoxin receptor-immunoglobulin and BAFF, as discussed below, are currently
in clinical trials Interestingly, the efficacy observed in RA patients treated with etanercept, which binds to
lymphotoxin-α as well as tumour necrosis factor (TNF)-lymphotoxin-α, may partly be related to blockade of the former cytokine [5] Simultaneous blockade of more than one factor that drives B-cell accumulation may be a more efficient therapeutic approach than targeting a single cytokine or chemokine
The role played by B cells in the maintenance of ectopic germinal centre-like structures, as well as in the immune response in RA synovium, has been addressed by using a humanized experimental model in which synovial tissue derived from patients was implanted into severe combined immunodeficient (SCID) mice [6] B cells were then depleted
by administration of anti-CD20 (rituximab), and T-cell responses were measured The removal of B cells led to disruption of the lymphoid-like structures and to a reduction
in T-helper (Th)1 interferon-γ producing cells, which are known to be involved in the induction and maintenance of the proinflammatory cytokine cascade
Role played by B cells as antigen-presenting cells in rheumatoid arthritis
B cells actively participate in an autoimmune process through interaction with T cells by a variety of mechanisms, including antigen presentation and cytokine production B cells process antigens, which are presented to T cells via major histocompatibility complex class II Inherited susceptibility to
RA has been associated with DRB1 genes that encode the
Review
Cells of the synovium in rheumatoid arthritis
B cells
Claudia Mauri and Michael R Ehrenstein
Centre for Rheumatology Research, Department of Medicine, University College London, Cleveland Street, London, W1T 4JF, UK
Corresponding authors: Claudia Mauri, c.mauri@ucl.ac.uk, or Michael R Ehrenstein, m.ehrenstein@ucl.ac.uk
Published: 5 March 2007 Arthritis Research & Therapy 2007, 9:205 (doi:10.1186/ar2125)
This article is online at http://arthritis-research.com/content/9/2/205
© 2007 BioMed Central Ltd
RA = rheumatoid arthritis; BAFF = B cell-activating factor of the TNF family; NP = hapten 4-hydroxy-3-nitro-phenyl acetyl; CCP = cyclic citrullinated peptide; CFA = complete Freund’s adjuvant; CIA = collagen-induced arthritis; CXCL = CXC chemokine ligand; FcγR = Fcγ receptor; IL = inter-leukin; IVIG = intravenous IgG; PG = prostaglandin; RF = rheumatoid factor; SCID = severe combined immunodeficient; Th = T-helper (cell); TLR = Toll-like receptor ligand; TNF = tumour necrosis factor;
Trang 2HLA-DR4 and HLA-DR1 molecules [7] These findings
suggest a pathogenic role for antigen presentation in RA
Although dendritic cells are believed to be important in
priming nạve T cells, B cells represent the predominant
population of antigen-presenting cells in later phases of the
immune response [8] Rheumatoid factor (RF)-producing B
cells are particularly effective in presenting immune
complexes to T cells, irrespective of the antigen contained in
the antigen-antibody complex [9] Thus, T cells of other
specificities could easily be activated if immune complexes in
RA contain other antigens
T-cell priming by B cells has been shown to be important in the
pathogenesis of a murine model of arthritis Specifically, the
involvement of B cells in priming T cells was dissected within
the context of proteoglycan (PG)-induced arthritis by using a
mouse deficient in a secretory antibody (mIgM) [10] These
mice express a membrane-bound heavy chain transgene,
which pairs with an endogenous light chain specific for hapten 4-hydroxy-3-nitro-phenyl acetyl (NP) T cells isolated from PG-immunized mIgM mice failed to induce arthritis in SCID mice, even if they were co-transferred with wild-type B cells, suggesting that T cells do not become properly primed in this experimental setting However, targeting PG to B cells using
NP coupled with PG led to differentiation of arthritogenic T cells that are able to transfer disease Other antigen-presenting cells could not substitute for B cells in this T-cell priming, supporting a central role for B cells in driving autoreactive T cells Autoantibody production was also essential for development of severe disease, indicating that B cells play two complementary roles in the pathogenesis of arthritis
Immune complexes can activate B cells via Toll-like receptor ligands
It was recently shown that chromatin-containing immune complexes can activate B cells through Toll-like receptor
Figure 1
B cell participation in RA Illustrated is the potential role of B cells in the regulation of immune responses in RA Mature B cells, upon antigen encounter and TLR stimulation, expand and differentiate into short-lived plasma cells or can enter into a GC reaction, which is necessary for the generation of both memory B cells, and long-lived plasma cells that can produce autoantibodies Autoantibodies form immune complexes that further activate the immune system via Fc and complement receptors expressed on target cells Antigen-activated mature B cells provide help to T cells and induce differentiation of effector T cells that produce proinflammatory cytokines (known to be directly/indirectly involved in cartilage and bone destruction) Mature B cells, via mechanisms yet to be elucidated, can also differentiate into IL-10 producing B cells that can dampen the autoreactive T-cell response GC, germinal centre; IFN, interferon; IL, interleukin; RA, rheumatoid arthritis; TLR, Toll-like receptor ligand; TNF, tumour necrosis factor
Trang 3ligand (TLR)9 These immune complexes activate B cells to
produce RF by synergistic engagement of B-cell receptor
and TLR9 [11] TLRs were originally described as a family of
pattern-recognition receptors that can differentiate between
microbial molecular patterns and host components [12] Their
engagement results in rapid activation of the innate and
adaptive immune systems to effect clearance of pathogens
There is mounting evidence suggesting involvement of TLR
signalling in the pathogenesis of experimental arthritis Mice
deficient for MyD88, the essential adaptor molecule involved
in signalling by TLR family members, failed to develop
streptococcal cell wall induced arthritis, and TLR2-deficient
mice exhibited reduced disease [13] Furthermore, direct
injection of CpG DNA or double-stranded RNA into joints of
susceptible mice results in the development of transient
arthritis [14] Heat shock protein, fibrinogen and hyaluronan,
which are known to bind to TLR4, have all been detected in
the inflamed joint [15] In the KB×N model of murine antibody
transferred arthritis, TLR4-deficient mice exhibit reduced
disease [16] Although there is enough evidence from
experimental arthritis implicating TLRs in the development of
arthritis, whether TLR activation is involved in human RA
remains to be formally demonstrated
Autoantibodies as effector molecules in
rheumatoid arthritis
The pathological involvement of antibodies in inflammatory
arthritis was first proved using DBA/1 mice immunized with
collagen type II in complete Freund’s adjuvant (CFA) These
mice develop a severe arthritis that shares some pathological
features with human RA It has been demonstrated that SCID
mice (which lack T and B cells), when treated with serum
isolated from arthritic DBA/1 mice, develop an inflammatory
arthritis [17,18] However, the disease was transient and less severe than collagen-induced arthritis (CIA) A more severe arthritis can be induced in recipient mice if serum is cotransferred with T cells presensitized with heat denatured collagen [19]
The pathological relevance of B cells in arthritis was further demonstrated by Holdhmal and colleagues [20], using µMT mice (which lack B cells) immunized with type II collagen in CFA Lack of B cells completely prevented induction of arthritis and resulted in an impaired T-cell response to type II collagen (Mauri C, unpublished data); this suggests that although autoantibodies can initiate disease, other compo-nents of the immune system are needed to fuel the pathogenic response
Compared with evidence from experimental models of arthritis, proof that antibodies are also pathogenic in human
RA is more difficult to obtain The presence of RF in serum, which binds to the constant region of IgG, was first identified
in 1957 [21] and has long been recognized as a marker in the majority of patients with RA The severity of RA has been correlated with RF levels, and patients who are seropositive for RF have more aggressive disease and worse prognosis [22,23] Important studies have indicated that the presence
of RF can be detected many years before arthritis begins [24,25]
The possible pathogenic role of RF-positive B cells has been revisited with the increased use of rituximab in RA therapy RF can cause tissue damage through formation of immune complexes, by activation of complement, thereby recruiting cells into the synovium Although preliminary data suggested that patients who are RF negative appear less likely to respond to B-cell depletion therapy [26], a larger trial [27] did not identify substantial differences in the response between RF-positive and RF-negative patients with RA However, RF titres fell by 55% in those patients who were RF positive, which corroborates previous findings [28] Moreover, routine assays for RF are not particularly sensitive and do not exclude their presence Thus, patients identified as being RF-negative may still have low titres of RF It is also possible that the many other autoantibody specificities present in patients with RA may distinguish those patients who respond to rituximab These other autoantibody specificities include those directed toward the nuclear antigen RA-33 and heavy chain binding protein, both of which are found in early RA and pre-disease sera [29] Antibody and T-cell reponses to heavy chain binding protein have been identified both in patients with RA and in animal models, suggesting that this may be an important autoantigen Although antibodies to type II collagen have been shown to induce disease in animal models, it is unlikely that anti-collagen antibodies are relavant to human disease Recently, antibodies to citrulline-modified peptides (anti-cyclic citrullinated peptide [CCP] antibodies) have attracted
Table 1
Potential targets driving B cell accumulation in the synovium
CXCL12 (SDF-1) B cell and plasma cell chemoattractant
CXCL13 B cell chemoattractant
Lymphotoxin-β Organization of B cells within lymphoid
architecture Induction of CXCL13
IL-5, IL-6, TNF-α Promote plasma cell accumulation and
survival
BAFF Immature and mature B cell survival and
proliferation
APRIL Mature B cell and plasma cell survival
TNF-α and IFN-γ Induces B cell release from bone marrow
Increased production of BAFF and APRIL
APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor of
the TNF family; CXCL, CXC chemokine ligand; IFN, interferon;
IL, interleukin; TNF, tumour necrosis factor
Trang 4considerable attention, and their measurement has now
entered into routine clinical use From a clinical perspective,
anti-CCP antibodies represent a useful test for predicting
which patients with early arthritis will go on to develop RA
The presence of both anti-CCP antibodies and RF predicts
the development of RA in patients with early arthritis with
high sensitivity and specificity [25] The importance of
anti-CCP antibodies is further emphasized by their link with
HLA-DRB1 shared epitope alleles, the most important genetic risk
factor for RA Recent work has suggested that this HLA
genetic risk factor is linked to the development of anti-CCP
antibodies rather than to the disease itself [30] Thus, the
presence of these autoantibodies in RA, often preceding
disease by many years, may indicate a breakdown in central
and/or peripheral tolerance
The pathological role played by anti-CCP antibodies was
recently confirmed in the CIA arthritis model As in human RA,
anti-CCP antibodies can be detected before the onset of
disease and are present in inflamed synovium of mice in the
acute phase of CIA Although the amount of anti-CCP
antibodies measured in serum of mice with acute
inflammation is similar to levels of antibodies to collagen type
II, transfer of anti-CCP antibodies alone failed to induce
disease in recipient mice However, transfer of anti-CCP
antibodies to SCID mice significantly reduced the amount of
anti-collagen type II antibodies necessary to induce disease,
demonstrating a contributing role in the development of
arthritis [31] The relevant targets of these antibodies in joints
or in peripheral tissue remain unknown
Are both Fc receptors and complement
component C5a required for autoantibodies
to drive the effector phase in arthritis?
Antibodies can act directly on target organs and induce
disease through Fc-mediated activation of the complement
system or through the formation of immune complexes In
addition, antibodies can directly activate Fcγ receptors
(FcγRs) expressed on both myeloid and lymphoid cells A
clear insight into how antibodies work in arthritis has been
gleaned from the K/B×N model of RA In these mice
glucose-6-phosphate isomerase (GPI) is the target autoantigen, and
T-cell reactivity to this ubiquitous antigen results in
recruitment of anti-GPI B cells and subsequent immune
complex-mediated arthritis [32,33] Arthritis can be induced
in non-autoimmune recipients, or in RAG2-/-mice (which lack
both T and B cells), by transfer of sera or purified antibodies
Similar to the SCID model mentioned above, inflammation
begins to subside between 15 and 30 days after antibody
transfer Histologically, analysis of joints 30 days after transfer
revealed less inflammation than in the K/B×N model itself,
and little cartilage damage, supporting the notion that other
abnormalities in cellular types and soluble factors are needed
for full expression of disease [32] FcγRs are intimately
involved in the pathogenesis of this arthritis In particular,
much milder arthritis was observed in mice lacking the FcγRIII
receptor [34], whereas FcγRII-deficient mice exhibited acce-lerated disease
The involvement of FcγRIIB in mediating antibody damage has also been investigated in the CIA model of arthritis FcγRIIB is an inhibitory receptor that suppresses B cells, mast cells and macrophages, and transmits its inhibitory signal via its immunoreceptor tyrosine-based inhibitory motif Deletion of FcγRIIB renders DBA/1 mice more susceptible to disease [35] Recently, the pathogenicity of human RA-associated antibodies was also tested in a passive transfer model using FcγRIIB deficient mice Transfer of serum from active RA patients, or an immunoglobulin-rich fraction, to 8- to 12-week-old B6.FcγRIIB-/- mice induced a mild transient arthritis [36], indicating that serum from patients with RA can induce an inflammatory arthritis The administration of a large amount of intravenous IgG (IVIG) is a common treatment for a number of autoimmune conditions and is thought to modulate
Fc receptor function [37] IVIG has been shown to have a protective effect in the K/B×N mouse model of arthritis discussed above through induction of FcγRIIB [38] This property of IVIG has been linked to sialylation of the Fc portion of IgG The proportion of sialylated IgG molecules in commercial IVIG may account for the very mixed results obtained when patients with RA were treated with IVIG [39] Involvement of the complement system in the development of mouse models of arthritis caused by autoantibodies has been demonstrated using C5-deficient mice Both the K/B×N and collagen-induced model of arthritis are dependent on C5a for disease expression, and antibodies to C5 ameliorated disease in the K/B×N model [40,41] This has led to clinical trials of C5a receptor based peptides in RA, with mixed results Other components of the complement system such
as C4 do not participate in disease pathogenesis [40] Therefore, the effector function of arthritogenic antibodies rely both on Fc receptors and C5a
Immunoregulation by B cells
Although the pathogenic role played by mature B cells in RA has been extensively studied, new data have demonstrated that a distinct subset of B cells, namely those that produce IL-10, are involved in the downregulation of the immune system It was originally demonstrated that B-cell-deficient mice developed an exacerbated experimental autoimmune encephalomyelitis as compared with wild-type animals, suggesting a protective role for B cells in the development of autoimmune disease [42] B cells that produce cytokines, and in particular IL-10, have been reported to play an immunoregulatory role in autoimmunity, chronic inflammatory bowel disorders, asthma and infectious diseases [43,44] In the context of arthritis, we previously showed that stimulation
of splenic B cells isolated during the acute phase of disease, with an agonistic anti-CD40 antibody, induces differentiation
of IL-10 producing B cells Transfer of anti-CD40 stimulated
B cells to DBA/1 mice immunized with collagen type II in CFA
Trang 5prevented or ameliorated arthritis [45] The mechanisms by
which this subset of B cell regulates the immune response
against autoantigens are not fully understood However, we
showed that mice treated with anti-CD40 challenged B cells
exhibit an impaired Th1 response [45] Therefore one
plausible explanation is that production of IL-10 might restore
the dysregulated Th1/Th2 balance, or it could directly
modulate effector cells, including macrophages and dendritic
cells, thus downmodulating inflammatory responses IL-10
producing B cells could also act as secondary
antigen-presenting cells, leading to an abortive response and
induction of anergic CD4+ T cells, or they could recruit
regulatory T cells or induce their differentiation If an
equivalent population exists in humans, then removal of these
B cells by rituximab might be detrimental
Targeting bad B cells
An understanding of which B cells are relevant to the
pathogenesis of disease is important in designing therapeutic
strategies to target B cells The vast majority of B cells found
in peripheral blood are removed by rituximab, but the extent
and nature of B cell removal in other tissues in RA patients
remain to be established For example, experiments
conducted in monkeys revealed that B cells residing in
tissues are less effectively removed, and that memory B cells
are more resistant to depletion than nạve ones [46] Similar
observations have been made in murine studies using
anti-CD20, where marginal zone B cells, B1 cells and germinal
centre B cells are more resistant to depletion [47-49] As
mentioned above, it is likely that plasma cells that producing
RF are likely to be important in disease pathogenesis, but
their depletion by rituximab is hampered by lack of CD20
expression However, those plasma cells that have a short life
span rely on CD20-expressing B cell precursors for
continued renewal Examination of peripheral blood indicates
that CD19+CD20-plasmablasts decrease following rituximab
therapy [50] The observation that RF titres decrease
following rituximab treatment suggests that short-lived, rather
than long-lived, plasma cells are at least partly responsible for
their formation A number of factors are known to be
important in plasma cell survival, including cytokines such as
TNF-α and the cell adhesion molecule CD44 [51] Perhaps
use of anti-TNF-α together with rituximab may have
syner-gistic benefit through their combined targeting of B cells and
plasma cells, although infection-related side effects may
prohibit use of this combination
Antagonists to BAFF also lead to incomplete removal of
peripheral and lymphoid B cells in monkeys, with marginal
zone-like B cells being particularly susceptible to depletion
[52] Trials have begun to evaluate the anti-BAFF agent
belimumab (LymphoStat-B; Human Genome Sciences,
Rockville, MD, USA) in RA and have demonstrated limited
efficacy, perhaps because of incomplete blockade or
because other related B-cell survival factors such as a
proliferation-inducing ligand (APRIL) would not be affected
Conclusion
Renewed interest in B cells in RA has been initiated by a global B-cell-depleting agent, but it is likely that only a small proportion of B cells contribute to disease pathogenesis whereas others may actually be protective It is hoped that research in patients with RA using these new agents will reveal correlations between pathogenic B cell subsets and improvement in clinical disease activity, thereby enhancing our understanding of the role played by B cells in human disease
Competing interests
The authors declare that they have no competing interests
References
1 Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska
A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid
arthritis N Engl J Med 2004, 350:2572-2581.
2 Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon
WM, Goronzy JJ, Weyand CM: Lymphoid neogenesis in
rheumatoid synovitis J Immunol 2001, 167:1072-1080.
3 Tan SM, Xu D, Roschke V, Perry JW, Arkfeld DG, Ehresmann GR,
Migone TS, Hilbert DM, Stohl W: Local production of B lympho-cyte stimulator protein and APRIL in arthritic joints of patients
with inflammatory arthritis Arthritis Rheum 2003, 48:982-992.
4 Seki T, Selby J, Haupl T, Winchester R: Use of differential sub-traction method to identify genes that characterize the
pheno-type of cultured rheumatoid arthritis synoviocytes Arthritis
Rheum 1998, 41:1356-1364.
5 Buch MH, Conaghan PG, Quinn MA, Bingham SJ, Veale D, Emery
P: True infliximab resistance in rheumatoid arthritis: a role for
lymphotoxin alpha? Ann Rheum Dis 2004, 63:1344-1346.
6 Goronzy JJ, Weyand CM: Rheumatoid arthritis Immunol Rev
2005, 204:55-73.
7 Newton JL, Harney SM, Wordsworth BP, Brown MA: A review of
the MHC genetics of rheumatoid arthritis Genes Immun 2004,
5:151-157.
8 MacLennan IC, Gulbranson-Judge A, Toellner KM,
Casamayor-Palleja M, Chan E, Sze DM, Luther SA, Orbea HA: The changing preference of T and B cells for partners as T-dependent
anti-body responses develop Immunol Rev 1997, 156:53-66.
9 Roosnek E, Lanzavecchia A: Efficient and selective presenta-tion of antigen-antibody complexes by rheumatoid factor B
cells J Exp Med 1991, 173:487-489.
10 O’Neill SK, Shlomchik MJ, Glant TT, Cao Y, Doodes PD, Finnegan
A: Antigen-specific B cells are required as APCs and autoanti-body-producing cells for induction of severe autoimmune
arthritis J Immunol 2005, 174:3781-3788.
11 Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC,
Shlom-chik MJ, Marshak-Rothstein A: Chromatin-IgG complexes acti-vate B cells by dual engagement of IgM and Toll-like
receptors Nature 2002, 416:603-607.
12 Takeda K, Kaisho T, Akira S: Toll-like receptors Annu Rev
Immunol 2003, 21:335-376.
13 Joosten LA, Koenders MI, Smeets RL, Heuvelmans-Jacobs M, Helsen MM, Takeda K, Akira S, Lubberts E, van de Loo FA, van
den Berg WB: Toll-like receptor 2 pathway drives
streptococ-This review is part of a series on
Cells of the synovium in rheumatoid arthritis
edited by Gary Firestein
Other articles in this series can be found at http://arthritis-research.com/articles/
review-series.asp?series=ar_Cells
Trang 6cal cell wall-induced joint inflammation: critical role of myeloid
differentiation factor 88 J Immunol 2003, 171:6145-6153.
14 Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski A:
Intra-articularly localized bacterial DNA containing CpG motifs
induces arthritis Nat Med 1999, 5:702-705.
15 van der Heijden IM, Wilbrink B, Tchetverikov I, Schrijver IA,
Schouls LM, Hazenberg MP, Breedveld FC, Tak PP: Presence of
bacterial DNA and bacterial peptidoglycans in joints of
patients with rheumatoid arthritis and other arthritides
Arthri-tis Rheum 2000, 43:593-598.
16 Choe JY, Crain B, Wu SR, Corr M: Interleukin 1 receptor
dependence of serum transferred arthritis can be
circum-vented by toll-like receptor 4 signaling J Exp Med 2003, 197:
537-542
17 Stuart JM, Tomoda K, Yoo TJ, Townes AS, Kang AH: Serum
transfer of collagen-induced arthritis II Identification and
localization of autoantibody to type II collagen in donor and
recipient rats Arthritis Rheum 1983, 26:1237-1244.
18 Taylor PC, Plater-Zyberk C, Maini RN: The role of the B cells in
the adoptive transfer of collagen-induced arthritis from
DBA/1 (H-2q) to SCID (H-2d) mice Eur J Immunol 1995, 25:
763-769
19 Nandakumar KS, Backlund J, Vestberg M, Holmdahl R: Collagen
type II (CII)-specific antibodies induce arthritis in the absence
of T or B cells but the arthritis progression is enhanced by
CII-reactive T cells Arthritis Res Ther 2004, 6:R544-R550.
20 Svensson L, Jirholt J, Holmdahl R, Jansson L: B cell-deficient
mice do not develop type II collagen-induced arthritis (CIA).
Clin Exp Immunol 1998, 111:521-526.
21 Franklin EC, Holman HR, Muller-Eberhard HJ, Kunkel HG: An
unusual protein component of high molecular weight in the
serum of certain patients with rheumatoid arthritis J Exp Med
1957, 105:425-438.
22 van Zeben D, Hazes JM, Zwinderman AH, Cats A, van der Voort
EA, Breedveld FC: Clinical significance of rheumatoid factors
in early rheumatoid arthritis: results of a follow up study Ann
Rheum Dis 1992, 51:1029-1035.
23 Symmons DP, Silman AJ: Aspects of early arthritis What
deter-mines the evolution of early undifferentiated arthritis and
rheumatoid arthritis? An update from the Norfolk Arthritis
Register Arthritis Res Ther 2006, 8:214.
24 Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen JT:
When does rheumatoid disease start? Arthritis Rheum 1985,
28:485-489.
25 Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell
G, Stenlund H, Sundin U, van Venrooij WJ: Antibodies against
cyclic citrullinated peptide and IgA rheumatoid factor predict
the development of rheumatoid arthritis Arthritis Rheum 2003,
48:2741-2749.
26 De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G:
Efficacy of selective B cell blockade in the treatment of
rheumatoid arthritis: evidence for a pathogenetic role of B
cells Arthritis Rheum 2002, 46:2029-2033.
27 Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA,
Genovese MC, Keystone EC, Loveless JE, Burmester GR,
Cravets MW, et al.: Rituximab for rheumatoid arthritis
refrac-tory to anti-tumor necrosis factor therapy: Results of a
multi-center, randomized, double-blind, placebo-controlled, phase
III trial evaluating primary efficacy and safety at twenty-four
weeks Arthritis Rheum 2006, 54:2793-2806.
28 Cambridge G, Leandro MJ, Edwards JC, Ehrenstein MR, Salden
M, Bodman-Smith M, Webster AD: Serologic changes following
B lymphocyte depletion therapy for rheumatoid arthritis.
Arthritis Rheum 2003, 48:2146-2154.
29 Mewar D, Wilson AG: Autoantibodies in rheumatoid arthritis: a
review Biomed Pharmacother 2006, 60:648-655.
30 van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga
TW, Toes RE, de Vries RR: The HLA-DRB1 shared epitope
alleles are primarily a risk factor for anti-cyclic citrullinated
peptide antibodies and are not an independent risk factor for
development of rheumatoid arthritis Arthritis Rheum 2006, 54:
1117-1121
31 Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, Robinson
WH, Holers VM: Antibodies against citrullinated proteins
enhance tissue injury in experimental autoimmune arthritis J
Clin Invest 2006, 116:961-973.
32 Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C,
Mathis D: A new mouse model of rheumatoid arthritis:
organ-specific disease provoked by systemic autoimmunity
Ryu-machi 1997, 37:147.
33 Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C,
Mathis D: Organ-specific disease provoked by systemic
autoimmunity Cell 1996, 87:811-822.
34 Corr M, Crain B: The role of FcgammaR signaling in the K/B x
N serum transfer model of arthritis J Immunol 2002, 169:
6604-6609
35 Kleinau S, Martinsson P, Heyman B: Induction and suppression
of collagen-induced arthritis is dependent on distinct
fcgamma receptors J Exp Med 2000, 191:1611-1616.
36 Petkova SB, Konstantinov KN, Sproule TJ, Lyons BL, Awwami
MA, Roopenian DC: Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor Fc gamma
RIIB J Exp Med 2006, 203:275-280.
37 Samuelsson A, Towers TL, Ravetch JV: Anti-inflammatory activ-ity of IVIG mediated through the inhibitory Fc receptor.
Science 2001, 291:484-486.
38 Kaneko Y, Nimmerjahn F, Ravetch JV: Anti-inflammatory activity
of immunoglobulin G resulting from Fc sialylation Science
2006, 313:670-673.
39 Braun-Moscovici Y, Furst DE: Immunoglobulin for rheumatic
diseases in the twenty-first century: take it or leave it? Curr
Opin Rheumatol 2003, 15:237-245.
40 Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA,
Takahashi K, Holers VM, Walport M, Gerard C, et al.: Arthritis critically dependent on innate immune system players
Immu-nity 2002, 16:157-168.
41 Grant EP, Picarella D, Burwell T, Delaney T, Croci A, Avitahl N,
Humbles AA, Gutierrez-Ramos JC, Briskin M, Gerard C, et al.:
Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in
experi-mental arthritis J Exp Med 2002, 196:1461-1471.
42 Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr: Experimental autoimmune encephalomyelitis induction in genetically B
cell-deficient mice J Exp Med 1996, 184:2271-2278.
43 Pistoia V: Production of cytokines by human B cells in health
and disease Immunol Today 1997, 18:343-350.
44 Mizoguchi A, Bhan AK: A case for regulatory B cells J Immunol
2006, 176:705-710.
45 Mauri C, Gray D, Mushtaq N, Londei M: Prevention of arthritis
by interleukin 10-producing B cells J Exp Med 2003,
197:489-501
46 Vugmeyster Y, Beyer J, Howell K, Combs D, Fielder P, Yang J,
Qureshi F, Sandlund B, Kawaguchi L, Dummer W, et al.:
Deple-tion of B cells by a humanized anti-CD20 antibody PRO70769
in Macaca fascicularis J Immunother 2005, 28:212-219.
47 Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM,
Tedder TF: The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent
mechanisms during anti-CD20 antibody immunotherapy J
Exp Med 2004, 199:1659-1669.
48 Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, Lin WY, Hu Z,
Lu Y, Chen Y, et al.: Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy J Immunol
2005, 174:817-826.
49 Hamaguchi Y, Uchida J, Cain DW, Venturi GM, Poe JC, Haas KM,
Tedder TF: The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20
immunotherapy in mice J Immunol 2005, 174:4389-4399.
50 Leandro MJ, Cooper N, Cambridge G, Ehrenstein MR, Edwards
JC: Bone marrow B-lineage cells in patients with rheumatoid
arthritis following rituximab therapy Rheumatology (Oxford)
2007, 46:29-36.
51 Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac
M, Muehlinghaus G, Szyska M, Radbruch A, Manz RA: Plasma cell survival is mediated by synergistic effects of cytokines
and adhesion-dependent signals J Immunol 2003,
171:1684-1690
52 Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S,
Nelson T, Martin F, Grewal I, Gilkerson E, et al.: A soluble BAFF
antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in
cynomolgus monkeys Am J Pathol 2006, 168:476-489.